Certain cells in the body respond not only to chemical signals, but also to ions such as extracellular calcium ions (Ca2+). Extracellular Ca2+ is under tight homeostatic control and regulates various processes such as blood clotting, nerve and muscle excitability, and proper bone formation.
Calcium receptor proteins enable certain specialized cells to respond to changes in extracellular Ca2+ concentration. For example, extracellular Ca2+ inhibits the secretion of parathyroid hormone (PTH) from parathyroid cells, inhibits bone resorption by osteoclasts, and stimulates secretion of cacitonin from C-cells.
PTH is the principal endocrine factor regulating Ca2+ homeostasis in the blood and extracellular fluids. PTH, by acting on bone and kidney cells, increases the level of Ca2+ in the blood. This increase in extracellular Ca2+ then acts as a negative feedback signal, depressing PTH secretion. The reciprocal relationship between extracellular Ca2+ and PTH secretion forms an important mechanism maintaining bodily Ca2+ homeostasis.
Extracellular Ca2+ acts directly on parathyroid cells to regulate PTH secretion. The existence of a parathyroid cell surface protein which detects changes in extracellular Ca2+ has been confirmed. (Brown et al., Nature 366:574, 1993.) In parathyroid cells, this protein, the calcium receptor, acts as a receptor for extracellular Ca2+, detects changes in the ion concentration of extracellular Ca2+, and initiates a functional cellular response, PTH secretion.
Extracellular Ca2+ can exert effects on different cell functions, reviewed in Nemeth et al., Cell Calcium 11:319, 1990. The role of extracellular Ca2+ in parafollicular (C-cells) and parathyroid cells is discussed in Nemeth, Cell Calcium 11:323, 1990. These cells were shown to express similar calcium receptors. (See, Brown et al., Nature 366:574, 1993; Mithal et al., J. Bone Miner. Res. 9, Suppl. 1, s282, 1994; Rogers et al., J. Bone Miner. Res. 9, Suppl, 1, s409, 1994; Garrett et al., Endocrinology 136:5202–5211, 1995.) The role of extracellular Ca2+ on bone osteoclasts is discussed by Zaidi, Bioscience Reports 10:493, 1990.
The ability of various molecules to mimic extracellular Ca2+ in vitro is discussed in references such as Nemeth et al., in “Calcium-Binding Proteins in Health and Disease,” 1987, Academic Press, Inc., pp. 33–35; Brown et al., Endocrinology 128:3047, 1991; Chen et al., J. Bone Miner. Res. 5:581, 1990; and Zaidi et al., Biochem. Biophys. Res. Commun. 167:807, 1990.
Nemeth et al., PCT/US92/07175, International Publication Number WO 93/04373, Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959, and Nemeth et al., PCT/US94/12117, International Publication Number WO 95/11211, feature calcium receptor-active molecules and refer to calcilytics as compounds able to inhibit calcium receptor activity. For example, WO 94/18959 on page 8, lines 2–13 asserts:                Applicant is also the first to describe methods by which molecules active at these Ca2+ receptors can be identified and used as lead molecules in the discovery, development, design, modification and/or construction of useful calcimimetics or calcilytics which are active at Ca2+ receptors. Such calcimimetics or calcilytics are useful in the treatment of various disease states characterized by abnormal levels of one or more components, e.g., polypeptides such as hormones, enzymes or growth factors, the expresssion and/or secretion of which is regulated or affected by activity at one or more Ca2+ receptors.        
The references provided in the background are not admitted to be prior art to the pending claims.